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Ulcerative colitis (UC) is chronic inflammation of large intestine and often requires lifelong medication. Medical therapy aims to induce and maintain a clinical remission, reduce the risk of colorectal cancer and improve quality of life. Aminosalicylates are currently the first choice therapy both for the induction and the maintenance of remission in the patients with mild-to-moderate UC. For moderate-to-severe cases or those who do not respond to aminosalicylate therapy, additional treatment options including corticosteroids, immunomodulators, biological agents, cyclosporin, tacrolimus and surgery are available. Poor adherence to medication has been an important barrier to successful management of UC. Nonadherence has been associated with increased relapse rates, higher risk of colorectal cancer, poor quality of life and significantly increased healthcare costs. Therefore, improving adherence to medication is an important approach for a better care of the patients with UC. Definitive strategies are required to help the patients effectively self manage their disease and improve adherence. This review examines current medical therapy for UC, research progresses on medication adherence and the possible strategies for improving adherence in these patients.

Norfolk and Norwich University Hospital, University of East Anglia, Norwich UK

Introduction

Ulcerative colitis (UC) is a chronic inflammatory condition causing continuous mucosal inflammation of the colon without granulomas on biopsy, affecting the rectum and a variable extent of the colon in continuity, which is characterized by a relapsing and remitting course [1]. Patients typically present with bloody diarrhoea and abdominal cramping [2–4]. The geographical incidence of UC varies considerably between 0.5 and 24.5 per 100 000 population, with a reported prevalence up to 246 per 100 000 population. The highest incidence rates were reported in Northern and Western Europe as well as North America, whereas lower rates were recorded in Africa, South America and Asia [5–7]. The incidence in Eastern European countries ranges from 0.5 to 5.9 per 100 000 population whereas countries of Western Europe have an overall incidence of UC of 10.4 [5,8–12]. Recent data from Southern Europe [11,12], Eastern Europe [5] and Asia [6,7] suggest that the new cases diagnosed with UC annually have been increasing in many developing countries [6,12,13]. Like many other long-term medical conditions, UC is disabling and disruptive to daily life of patients. It places considerable demands on the healthcare service and is associated with increased healthcare costs [14,15]. About 50% of the patients with UC have a relapse in any year, and the 10-year cumulative relapse rate of patients with at least one relapse range from 67 to 97% [3,4,16–19]. An appreciable minority has frequently relapsing or chronic, continuous disease and, overall, about 20–30% of the patients need colectomy but lower rates have been reported recently in an unselected European cohort that was followed for 10 years [20]. It has been shown that UC is associated with increased mortality from digestive diseases other than inflammatory bowel disease and male patients have a significantly increased rate of death because of colorectal cancer although this was not observed in female patients [21].

The primary aims of medical therapy for the patients with UC are directed at inducing and then maintaining remission of symptoms and mucosal inflammationto provide an improved quality of life with the least amount of steroid exposure [22]. Effective medical management and maintenance therapy may also help with restoring nutritional balance, timing surgical therapy and reducing the risks of complications such as colorectal cancer [3,23,24]. Recent studies have shown that poor adherence has been an important barrier to successful management of the patients with UC [25,26]. Only 40–60% of the patients who were newly diagnosed or had longstanding disease are adherent to therapy [27–30]. Although patients at all stages of UC are affected by nonadherence, those in symptomatic remission are particularly at risk of poor adherence, often taking less than 70% of their prescribed medication [27,28,31,32]. It is not surprising that nonadherent patients are five times more likely to have an exacerbation of disease compared with adherent patients, and are associated with significantly increased healthcare costs [26,33]. Improving medication adherence has become one of the most important steps in the effective management of the disease. Although many studies have assessed the factors that are related to poor adherence among these patients, interventions or strategies that can be used for improving poor adherence have not been fully explored and discussed. This review therefore examines current medical therapy for the patients with UC, research progresses on medication adherence and the possible strategies for improving adherence in these patients.

Search strategy and selection criteria

A PubMed search was performed with the medical subject heading terms ‘inflammatory bowel disease’, ‘UC’, ‘adherence’, ‘compliance’, ‘self-management’ and ‘self-care’. Citations that discuss medical therapies including induction and maintenance management, medication adherence and the strategies for improving self-management and adherence of the patients with UC were included. Where relevant systematic review articles were available and studied, their references were examined for additional papers.

Medical management

The activity and the distribution of UC, the pattern of the disease and the preference of the patient are the main factors to be considered in making therapeutic choices for newly diagnosed cases. For those who experience relapse, the best treatment option may be to use the therapy that worked earlier [3,23]. The disease activity is usually defined as remission, mild, moderate or severe [4,34,35]. Several scoring systems are used for clinical trials to assess the disease activity, which have been recently reviewed in detail by D'Haens and colleagues [36]. The simplest, best validated and most widely used index remains the Truelove and Witts scores [34–36]. Its accuracy for identifying severe UC makes it particularly relevant in clinical practice to distinguish the patients with severe UC necessitating hospital admission from those with mild or moderate disease who can generally be treated as outpatients [3,23]. The distribution of the disease is determined by the involvement of inflammation and is usually classified as proctitis, left-sided and extensive colitis that extends proximal to the splenic flexure including pancolitis [1,4]. The distribution is assessed by colonoscopy for those who have mild-to-moderate disease. Owing to the risk of bowel perforation in moderate-to-severe patients, it may be appropriate, however, to defer the investigation until the clinical condition improves [3]. The newly published European guidelines have suggested that it should be a standard practice to confirm active colitis by sigmoidoscopy or proctoscopy before starting treatment [23].

The patients with active UC will need medication to induce remission. Aminosalicylates including mesalazine, sulphasalazine, olsalazine and balsalazide are the standard treatment for the induction of remission in mild-to-moderate UC patients [3,23,37]. Oral aminosalicylates are available for the management of UC in a range of formulations with different release characteristics, but comparable pharmacokinetics in terms of systemic absorption, urinary excretion and faecal excretion. They have all demonstrated an equal efficacy in extensive and left-sided colitis [23,37,38]. A recent updated Cochrane meta-analysis of aminosalicylates has further confirmed the efficacy of these agents as compared with placebo for inducing remission [37,39].

The choice of particular aminosalicylate formulation/preparation to be used for the patients with UC may largely depend on the distribution of the disease. This is because different formulations/preparations release mesalazines at different sites in the gastrointestinal tract. Depending on the location of inflammation, one formulation may be more suitable than the other [37,40,41]. The patients with distal involvements may benefit more from a rectal preparation [23,37]. Increasing data have suggested that combined oral and rectal aminosalicylate therapy may be associated with a better clinical response even for the patients with extensive colitis as compared with oral treatment alone [23,37]. Marteau and colleagues [42] have recently compared the effectiveness of combined oral and enema Pentasa (mesalazine) treatment with oral therapy alone in patients having extensive mild to moderate UC in a randomized, double blind, placebo-controlled clinical trial of 127 ambulatory patients. All participants received 4 g/day (twice daily dosing) oral mesalazine for 8 weeks. During the initial 4 weeks, they additionally received an enema at bedtime containing 1 g of mesalazine or placebo. Disease activity was assessed using the ulcerative colitis disease activity index (UCDAI) [35], with clinical and endoscopic assessment at 4 and 8 weeks. Remission was defined as a UCDAI score less than 2. Improvement was defined as a decrease in the UCDAI score by more than or equal to 2 points from baseline. They found that the combination therapy is superior to oral therapy alone for both inducing remission and improvement [42]. Similar results have also been reported by several other research groups [43–46]. The choice of individual aminosalicylate may also be affected by factors such as the cost to the patient, patient preference and doctor experience [37,47,48].

The optimal dosing of 5-aminosalicylic acid (5-ASA) may depend on the severity and the distribution of UC. A systematic review and meta-analysis have shown that mesalazine therapy may induce remission and clinical improvement in a dose-responsive manner [39]. Hanauer and colleagues [49] have assessed whether an initial dose of 4.8 g/day mesalazine is more effective for inducing remission than 2.4 g/day in the patients with active UC in a randomized, double-blind, controlled trial (ASCEND I). They randomly assigned 301 adult patients with mild-to-moderate UC to delayed-release oral mesalazine 2.4 g/day or 4.8 g/day therapy for 6 weeks. The primary efficacy end point was overall improvement (i.e. treatment success), defined as complete remission or response to therapy from baseline to week 6. They found that 4.8 g/day therapy achieved a statistically higher rate of treatment success than those who received oral mesalazine 2.4 g/day at week 6 only in the patients with moderate, but not mild UC [49]. Other studies have also showed that in the patients with moderate UC, higher doses of mesalazine induced faster relief of symptoms (e.g. stool frequency and rectal bleeding) and mucosal healing as assessed by endoscopy [49–51]. The results, however, from several other clinical trials do not support the above findings. These trials compared the efficacy of different doses of mesalazine on inducing remission using Multi Matrix System (MMX) mesalazine, a novel, high-strength mesalazine formulation that utilizes MMX technology to delay and extend delivery of the active drug throughout the colon. Although all these studies have confirmed that the MMX mesalazine given as 2.4 or 4.8 g/day once daily is well tolerated and effective for the treatment of mild-to-moderate UC, no statistic difference was observed between the two doses in their efficacy for inducing remission [52–55].

Corticosteroids are required for inducing remission in the patients who have moderate and more severe UC, do not respond to oral 5-ASA and/or rectal therapy, or are intolerant to 5-ASA. It may provide rapid symptom relief, but corticosteroids are not used for maintenance therapy due to its undesirable side effects [3,23,37]. Ho and colleagues [56] have assessed the clinical outcome after the first corticosteroid therapy. Both the early (30 days) and late (1 year) outcomes were studied among 136 UK patients with UC. They found that 75% of the patients required corticosteroid therapy. At day 30, 51%, 31% and 18% of the patients demonstrated complete response, partial response and no response, respectively. After 1 year, 55%, 17% and 21% demonstrated prolonged response, corticosteroid dependence or required surgery. Similarly, a study of 185 US patients has shown that at day 30, 54% had complete remission, 30% were in partial remission, and 16% had no response. At 1 year, 49% had prolonged response, 22% were corticosteroid dependence, and 29% had an operation [57].

The patients with severe UC and those who have failed on oral corticosteroids need to be admitted to hospital for intravenous corticosteroids [3,22,23,58]. The alternative medical therapies for the patients with severe UC, but unresponsive to intravenous steroids, include intravenous cyclosporin as a 24-h continuous infusion at doses of 2–4 mg/kg per day, oral tacrolimus, or infliximab at a dose of 5 mg/kg at week 0, week 2 and week 6 followed by maintenance treatment [2–4,22,23,58]. Methotrexate has been studied in the patients with active UC, but its efficacy for inducing remission is largely unproven [59,60].

It has been generally recommended that the patients in remission should receive maintenance therapy with aminosalicylates, azathioprine or mercaptopurine to reduce the risks of relapse and colorectal cancer [3,23,24]. Oral 5-ASA and other aminosalicylates are the first choice for maintenance therapy [3,22,23,37,38]. Daily doses of 1.5 g mesalazine, 2 g sulfasalazine, or 1 g olsalazine may be sufficient to maintain remission [61]. Recent studies have, however, shown that the remission lasted longer when the maintenance dose increased from 1.2 to 2.4 g/day, which was particularly of benefit to the patients with extensive disease [62]. A retrospective analysis also found that the frequency of relapse was lower in the patients taking more than the median dose of 5-ASA (1.6 g/day) compared with those taking less than the median dose [62]. Rectal mesalazine can be used as an alternative to oral dosing in the patients with left-sided colitis or proctitis. Patients who relapse while on oral aminosalicylates, those who are steroid-dependent and those who have severe UC requiring induction therapy with ciclosporin or tacrolimus can be treated with azathioprine or mercaptopurine [3,22,23,37,38]. Azathioprine at 2–3 mg/kg per day or mercaptopurine at 1.0–1.5 mg/kg per day are the usual doses used in these situations. Infliximab is effective for maintenance of remission and is steroid-sparing in the patients who are unable to maintain remission without steroid therapy, or are intolerant to immunosuppressive agents [63].

Medication adherence

Nonadherence to medication, defined as a patient's failure to follow a prescribed drug regimen, remains a significant concern for healthcare professionals and a common problem for patient care. On average, one third to one half of patients do not adhere to prescribed treatment regimens [64–66]. Low adherence to medication in the patients with UC has been well documented in many recent studies and recognized as an important barrier to successful management of the disease [25,26]. Kane and colleagues [33] prospectively studied the risk factors associated with relapse among 99 patients who were in remission for more than 6 months and prescribed for 5-ASA maintenance therapy. The clinical recurrence of UC was defined as four or more bowel movements per day. Based on a 24-month follow-up data, they found that nonadherence to prescribed medication was the most significant factor leading to relapse among the factors analysed. Nonadherent patients had more than a five-fold greater risk of relapse than adherent patients [42]. A UK-based cross-sectional study, using data extracted from general practitioner (GP) clinical records, examined the usage of long-term aminosalicylate therapy in the patients with UC [67]. It is found that 38% of the patients with extensive colitis, 37% of the patients with left-sided colitis and 46% of those with proctitis did not take medication for maintenance therapy. A difference in adherence to long-term therapy was also noticed between patients who were under secondary and primary care. Nineteen percent of those who had more extensive disease and were under regular hospital specialist care did not take 5-ASA, whereas 50% of those discharged to GPs were off maintenance therapy [67,68]. Similarly, Stone and colleagues [30] found in central England that only 65% of the patients with UC had been prescribed maintenance therapy and good treatment adherence was suggested in only 42% of these patients. Prescribing of aminosalicylates was more common for patients under specialist or shared care than those under GP care only. Bernal and colleagues [69–71] assessed the medication-taking behaviour in a cohort of 115 patients with Crohn's disease and 99 patients with UC in Spain. They found that the most prescribed medications were oral mesalazine (56.5%) and immunomodulators (41.1%). Forty-three percent of patients admitted to occasionally forgetting to take their medication and 7.5% of them were intentional nonadherent. Patients on oral mesalazine and azathioprine were the most commonly affected and the nonadherence rates were 45% and 25% of the total prescribed doses, respectively. Another European study on 210 patients has shown that the overall intentional nonadherence was 38.9% [70]. These data suggest that nonadherence to medication is a common problem in the patients with UC in European countries [72].

Although the clinical impact of nonadherence to medication in the patients with UC has been well established in North American [25,26], data from the UK and other European countries are limited. The economic impact of nonadherence to prescribed, long-term therapy for all diseases has been estimated to cost as much as $100 billion in the US each year and accounts for 10% of all hospital admissions [73–75]. However, there are no studies to directly assess the costs associated with nonadherence in the patients with UC. As one of the most important factors leading to relapse, the economic impact of nonadherence can be reasonably estimated based on the costs of managing a relapse of the disease [25]. Recently, it has been estimated in the UK that the relapse was associated with a two-fold to three-fold increase in the costs for those who did not require hospital care and a 20-fold increase for those who were hospitalized [14]. Patients who experience symptomatic relapse will also accrue costs associated with additional diagnostics and treatment [75].

Many factors have been related to increased risk of nonadherence in the patients with UC. A systematic review has shown that medication adherence can be affected by disease extent and duration, costs of medication, fear of adverse effects, individual psychosocial variables and the patient–physician relationship [76]. Forgetfulness, male sex, complicated dosing regimens, treatment delivery methods (oral vs. rectal), and pill burden have also been suggested by some studies [25,26]. A study of 98 outpatients receiving delayed-release mesalazine has found that depression was the only independent predictor of complete nonadherence, whereas three times daily dosing and full-time employment were associated with partial nonadherence [32]. Hall and colleagues [77], using semi-structured interviews and focus groups, have recently undertaken an in-depth analysis of patient's attitudes and beliefs about drug therapy and how this affected their medication behaviours in British patients with UC and Crohn's disease. The main emerging themes from the study centered on patient acceptance and the perceived necessity of their medication, the fears and concerns held about their medication, the perceived impact, actual or potential, that their illness and symptoms had on their lives and willingness to self-manage. It was suggested that a concordant approach including flexible and proactive support as well as accurate information is important in assisting patients to self-manage their medication effectively. Health professionals should be aware that attitudes to medicine taking and other related behaviours might be medicine specific and change with time. Furthermore, the views on the need for long-term maintenance therapy in the patients with UC may vary among physicians and this will have significant impact on the medication-taking behaviours of their patients. One study has suggested that 35% of the patients with UC were not prescribed for a long-term maintenance therapy by their doctors [30].

Strategies for improving medication adherence

Improving adherence has become one of the essential aspects for effective management of UC, given the high prevalence of nonadherence to medication in the patients with UC and its associated adverse effects on the risks of disease relapse and colorectal cancer, quality of life and healthcare costs in these patients. Strategies such as establishing a good therapeutic relationship between doctor and patient, simplification of treatment (e.g. reduced dosing frequency and the use of long-acting agents), pill checks and patient education have all been proposed in recent publications [25,26,76]. Interventions with demonstrated effectiveness in improving adherence and health outcomes among the patients with UC, however, remains lacking.

Providing patients with convenient dosing regimens and simpler less intrusive methods of drug delivery have been effective in improving adherence for patients with several chronic conditions, such as hypertension and osteoporosis [25]. In an attempt to increase the medication acceptability, novel oral and rectal formulations of 5-ASA such as the MMX mesalazine have been developed to allow once-daily treatment of mild-to-moderate UC [53,78]. The effectiveness of these new agents in improving adherence remains to be tested. Recent data, however, show that altering treatment-related factors such as daily dose, regimen and formulation may have little impact on adherence in the patients with UC, particularly for those on longer duration of medication [76]. This is best illustrated in a study of 94 patients with clinically quiescent UC for more than 6 months on 5-ASA maintenance. It was found that adherence rates were not affected by either the dose or the dose regimen of the medication [27].

Improvement in communication between physicians and patients and in patient education might enhance adherence to the therapy [79–83]. Poor or ineffectual patient–physician dialogue and inadequate patient education were found to increase the risk of intentional nonadherence in the patients with UC, as well as the risks of overall and unintentional nonadherence in psychologically non-distressed patients [29]. Although approaches to improve patient education and to establish an effective patient–physician relationship have been well discussed in recent review articles [25,26], physician education has hardly been discussed. In the UK, more than one-third of the patients with UC have not been prescribed long-term maintenance medication by their doctors [30]. A significant difference of adherence rates between patients who were under the care of GPs alone and those followed in secondary care has also been reported [30,67,68]. These findings indicate that education of physicians and GPs may be necessary and important in improving adherence to medication in the patients with UC [67,68].

Furthermore, controversies exist in the role of long-term maintenance therapy in managing the patients with quiescent UC [84]. In fact, data that support the benefit of long-term maintenance therapy in reducing the relapse are weak and largely based on one early study [85] and several small trials [86]. This has been recently wellreviewed [23,86]. Other studies also suggests that for the patients in remission for more than 2 years it may be reasonable to stop using maintenance therapy [84]. In contrast to the findings from medication adherence studies, a recent report suggests that the 10-year cumulative relapse rates in the patients not using 5-ASA maintenance therapy were actually lower than those on medication [16]. The evidence for the role of maintenance therapy in preventing colorectal cancer is consistent. The data, however, were all from case-control studies with many inherent limitations. It has not been possible to conduct a randomised control trial because of ethical constrains [24]. Therefore, although current guidelines indicate that life long therapy is required, it is not difficult to understand that, with all the above confusions, both patients and physicians may choose to stop the therapy at some point. After all, the UK guidelines also suggest that in some cases of UC, it may be reasonable to stop the use of maintenance therapy [3]. Data on medication adherence of the patients with UC from the UK were mainly obtained before the publication of the British guidelines [3], it may be of interest to know whether the guidelines have any impact on the adherence of the patients with UC [25,26,76]. Further research is also required for the need of maintenance therapy in the patients with quiescent UC.

Successful management of UC, as with all other chronic illness, relies on effective patient self-management. Outside of the hospital environment patients are responsible for managing the day-to-day disease-related problems, such as fitting in treatment with work, education, family life and coping with the symptoms of the condition. Increasing recognition that self-care constitutes an important aspect in the management of long-term illness is present. It has been shown that greater patient involvement in chronic disease management can lead to improved quality of life, better adherence to medication and reduced reliance on formally provided services [87,88]. Evidence that healthcare professionals can enable and support patients with chronic conditions to monitor their disease is present, adjust their treatment in response to changes and identify situations where medical intervention is advisable [82,89,90]. Guided self-management involving the provision of a shared set of guidelines containing action plans for prevention of disease activity and/or symptom relief have been used in the management of many chronic illnesses [91]. The guidelines are developed by patients and doctors in collaboration and recognize preferences and agreed treatments. The patient decides whether or not to follow any or all of the instructions in response to perceived or measured changes to their health. The benefits are reported to go beyond simple disease control. By providing the patient with a clear set of goals, guided self-management plans also give patients a basis for discussion and negotiation with the health provider and a framework within which to understand their disease [92]. The successful implementation of guided self-management requires a mutual acceptance by patients and health professionals of the value of the advocated approach to care [90,93], time to explain the practical aspects involved [94,95], willingness to share information freely [96], and understanding of the social, psychological and behavioural factors that influence patient concordance [97,98]. A guided self-management package on the patients with UC has been developed in the UK [82]. A 12-month multicentre cluster randomised controlled trial on this intervention package in 700 patients at 19 hospitals has shown that self-managing patients made fewer hospital visits and felt more able to cope with their condition [82,83,91]. Further study is necessary to assess whether such intervention will improve adherence to medication and clinical outcomes in the patients with UC.

Another reported potential strategy to improve adherence in the patients with UC is the use of a home telemanagement system. The system consists of a laptop for self-testing and a digital scale. A 6-month randomised controlled trial in the patients with UC and Crohn's disease has demonstrated the feasibility and the acceptability of the system. It has also shown the potential to improve adherence, patient–physician communication, patient education and quality of life in these patients [99]. The use of this system may be, however, limited by its high cost [100]. As technology develops, new and more convenient approaches to support patient self-management and education and improve medication adherence, may emerge.

Conclusion

UC is a chronic medical condition that may require patients to take medication throughout their lives to prevent relapse, reduce the risk of colorectal cancer and improve quality of life. Studies have, however, shown hat adherence to medication in these patients is poor. Nonadherence to the prescribed therapy has been shown to increase the risk of symptomatic relapse and healthcare costs and to adversely affect quality of life. Therefore, improving adherence has become one of the important approaches towards the effective management of the disease. The problem of adherence to medication is complex and may involve many factors such as disease extent and duration, cost of medications, fear of adverse effects, individual psychosocial variables and the patient–physician relationship. The associated factors may vary in each country because of the difference in the healthcare system and the population. Simpler and more convenient dose regimens delivered via a less intrusive formulation may not be as effective as expected in improving adherence for the patients with UC. For many patient populations, dynamic communication between the healthcare team and the patient is a key factor in fostering adherence with long-term medication regimens. A self-management package incorporating enhanced patient education and physician–patient interaction has been developed for the patients with UC. This may be a useful strategy to improve adherence in these patients. Utilization of home-based technologies may also aid in increasing adherence. In addition to patient education, continuing medical education of medical professionals who are involved in the care of the patients with UC is also required.